A new study shows inhibiting the kinase p38α using the small molecule drug neflamapimod, could potentially improve cognitive and motor function in patients with neurodegenerative diseases that affect cholinergic neurons in the basal forebrain. Cognitive decline during aging or in dementia with Lewy bodies (DLB) and motor dysfunction in Parkinson’s disease are associated with neurodegeneration of basal forebrain cholinergic neurons (BFCN).

Cholinergic neurons, with their long axonal projections dispersed throughout the cerebral cortex, are vulnerable to malfunctions of a retrograde signaling system mediated by the nerve growth factor (NGF) that transmits messages from distant synaptic connections back to the cell body. Pivotal to the proper function of NGF signaling and neurodegeneration of cholinergic neurons in the basal forebrain, is the GTPase called Rab5 that facilitates endocytosis, a process that pulls external substances into the cell. A phosphorylating enzyme (kinase) called p38alpha activates Rab5.

EIP Pharma, a biopharmaceutical company developing therapies for neurological diseases, together with scientists at the NYU Grossman School of Medicine tested the hypothesis that inhibiting the Rab5 kinase p38α can treat diseases associated with the loss of basal forebrain cholinergic neurons (BFCN).

Results from their preclinical and Phase IIa exploratory, randomized controlled trial (RCT) that tested the safety and efficacy of neflamapimod in a mouse model of BFCN degeneration and patients with mild to moderate DLB, were published in Nature Communications “Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration“. Neflamapimod is an oral, small molecule p38α inhibitor that penetrates into the brain that essentially amplifies the release of the neurotransmitter acetylcholine.

Senior author of the study, Ralph Nixon, MD, PhD, director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg NY, said, “The findings indicate that neflamapimod appears to represent a scientific breakthrough towards treating degeneration of the basal forebrain cholinergic system, a long-standing objective of drug development for a range of neurodegenerative diseases.”

Mouse models treated with neflamapimod showed reduced Rab5 activity which reversed the neurodegenerative process in the BFCN.  The 16-week double-blind RCT (Clinical trial registration#: NCT04001517/EudraCT #2019-001566-15) included 91 patients with DLB who all received background cholinesterase inhibitor therapy. The participants took oral pills of 40 mg neflamapimod or placebo capsules twice daily if they weighed less than 80 kg or three times a day if they weighed more.

The authors reported that neflamapimod did not affect performance in a cognitive-test battery—the primary endpoint of the RCT. However, participants showed improvements in secondary endpoints of the RCT that included a measure of functional mobility and a dementia rating scale. These improvements were consistent with an effect on BFCN function. The researchers also showed that the drug was safe and well-tolerated. No participants had to be taken off the treatment due to the drug-related side effects.

The authors concluded, “Combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory clinical evaluation of neflamapimod in DLB.”

Neflamapimod has been granted Fast Track status as a treatment for DLB by the FDA. EIP Pharma plans to start confirmatory Phase IIb clinical trials of neflamapimod for patients with DLB.

“We strongly believe in neflamapimod’s potential to play an important role in the treatment of neurodegenerative diseases, especially in DLB,” said John Alam, MD, scientific founder, and CEO of EIP Pharma. “The cholinergic system has long been known to be critical in the pathogenesis of dementia, and neflamapimod’s profile is well suited to become a foundational treatment in a disease like DLB, where there are no approved therapies.”

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